We will determine the mechanisms which cause breathing instability and central apnea during sleep and their effects on upper airway resistance, using chronically instrumented, unanesthetized dogs and human subjects. 1. How does central nervous system hypoxia affect the magnitude and stability of breathing pattern during wakefulness and sleep? We have developed a unique preparation for use in waking and sleeping dogs whereby the carotid chemoreceptor is perfused independently of the systemic and CNS circulations. 2. What mechanisms contribute to ventilatory instability and central apnea following perturbations in ventilatory output during sleep? We will examine the opposing effects of excitatory short-term potentiation vs the inhibitory effects of a) hypocapnia, b) vagal feedback from the lung and upper airway negative pressure and c) control system "inertia". 3. What is the role of carotid chemoreceptor hypocapnia, per se on respiratory motor output and timing? Using the isolated carotid chemoreceptor perfusion, we will test the role of steady-state and transient changes in hypocapnia on respiratory motor output in the awake and sleeping dog. 4. We will use passive and actively-induced hyperneas to determine the affect of transient changes in respiratory motor output and central apnea on upper airway patency and resistance in humans who represent a wide spectrum of susceptibility to airway closure. Sleep in humans is often characterized by marked and frequent fluctuations in ventilatory output and the drive to breathe, which has serious implications for sleep induced problems in gas exchange, sleep state stability and upper airway patency. We believe our proposed studies using commonly encountered perturbations in physiologic preparations provide a realistic and comprehensive approach to investigation of the complex mechanisms underlying sleep-disordered breathing and central apnea.